B-bromotheophylijne salt of z-amino-z-



Grote, Chattanooga, Tenn., assig'noi's fto The Chat tanooga MedicineCompany, Chattanooga, Tenm, a corporation of Tennessee No Drawing.

Serial No. 3 21,498 1 Claim. c1. 260-253 Application November 19, 1952,

' symptomsg i V iproductiof h pr'sent'ai tg ftion; -in-.the-treatment-ie a vpremenstrual,:tension is--;that in mostjpatients 'it; pro Thepresent invention relates, to a pharmaceutical compound having enhanceddiuretic activity,- and more particularly, totthe compound:8-bromotheophylline-2 amino-Z-methyl-l-propanol,which is abromotheophylgline salt of 2-amino-2-methyl-l propanol. "These.compounds have the following'structural formulas:

I 8-bromotheophylline cH3-N-c =ofH 2-amino-2-methyl-1-propanol i CH3 NH!cq nr -cm-c-wmon 1 been combined withflvarioujs amines for/the purposeof solubilizing'the theophylline in. diuretic compositions Probably the.most commomde'rivatiye ofwthis-Ltypeuis theophylline-ethylene v diamine,xknown aunder theiconl mercial name Aminoph'yllineff.

w are also awarethat s. Patent Ne. i,404,319,

issued July 16, 1946, to Robert S; Shelton, discloses :and

claims the theophyllineisalti-of u2t-methyl-2-amino-l-l propanol,alleging ,thatmthis compoundgis superi or to Aminophylline as: a.therapeuticaage'nt y We .have now found't'hat, if the-theophylline oithis type ,of composition is-replaced :by a -halotheophylline;

particularly 8-bromotheophylline, 'not only is "the solu t oft8-bromotheophylline areg suspended in one l terliof water. "To thissuspension are addecl eighty-ninegrams: V

bility of the resulting composition increased,- to a greater:

degree than occurs fromwthe; reaction between theophyl- 1 line and thesame amine fcompound, particularly 2-x methyl-Z-amino-l-propanol but 1the 1 resulting; salt-is fa1 superior as a diuretic compound tothepprevjiously known i n U l temvby t mw t Theremarkably increaseddiuretic properties;tofhthe 2 1 -1 9 halotheophylline-amine salt "of the1 present; invention makes it a valuable-therapeutic agent in the reliefof pre-} menstrual tension, a v condition upon which previously; 3 knownderivatives of theophylline hadlittlepr no efiect.

diuretic compounds containing theophylline; 1;

A large percentage of women, estirnated at 3.010)

V 1-; .T bii'f Q '1" th?f qemolesula I I compoundg has b eenformed-consisting oflone'mole bromoth a hylline combined jwith fone moleof g-amino extreme nervousness, swelling of the;ankles jncreased;

appetite, irritability; pelvic: pain, and 1 a feeling of tension. Theseverity of the-discomfornis:directly comw mensurate with the -ax nountof fluid .accurnulated sort; Pounds o i d-lwomenaw otze ime qm;

3 /2 to 4. pounds during the 7 week "preceding the are almostincapacitated gue to;v th symptoms'from water toxemia-.,- Z v V i TheCompound. of the hprese ntq nvven on ly efiicient inthe relic F withpremenstrual tension:

Patients to whom the com- -Lt ympt m :tasa t siit menstrual,periodgsi's-- 5. v I, Ang objectaof the p esent mvention sis oaprovidea sal2=amino+2-m ethy1 l -propanol, fOI' ause 3 intheire lief premenstrual;-tension without 1 {thev presence-11o side: tions usually associatedjwith-the- Jadmini eQphy lin a The salt. of these two compounds'maysbeScalIed -Z amino-Z-methyl-l-propanol '8 -bromotheophyllinate orturefis" well ifstirred and l if necessary completelsolutiou cow intesting the o ,be fexcreted' as urine overa;=four-h our period.

the, presentainvention is administered iapp .oxi week ;:b'eforethe Onsetof menses rarely E gai ning treatment,

.One outstandin erapeu vents waterf accumulation without diuresisygifithe treat ment isastarted: 'earlygenoughgso thattheipatients -have-i no;symptoms ofdwa'tergtoxemia throughon their prettherapeutic product'comprising a .halotheophylline;-salt ofa' organic;.amine,;namely, the8.-bromotheophylline fo si lne grams .Two hundred" all pared to Qtheor'etical -pro'pa nol accordingto'the"following formula 'c s'r-.CH. ;icH,-QH q The compound decomposes rrather sharply atv 390. 'C.

i The solubility? j wat'er at; froom temperature exceeds 30 31100 c. togive also'lution'havinga pH otaroun e e 7 mpound ot thevpresentinvention for, 1ts"d ur etic1 action, the ffollowing procedure 'wa'si'usedi When .rats are given-tap water perorallyQoh}the-;b'asi' rat, ontheaverage' of s-1 00% of the waterso given will 1 f,":in"- j addition'to the watc the rats areeachlgiven' sub- 3 cutaneously /2 unit 'ofpit're ssi'n, an anti-diuretic drug, only 42% of. the. .water,..on theaverage, will he ex: creted. In conducting this test, the drug to betested is given in a dosage on the basis of 0.1 g. of the product perkilogram'body weight of-the rat and the product isadded inthisproportion to :the water and pitressin. In this way, the anti=pitressinaction of each of the various compounds is tested in terms ofthc percentof water recovery from the rats. 1 3 a It was found that the diureticactivity of 8'-bromotheophyllineQemino-Lmethybl propanol was 116-;whereas the diuretic-activity of the corresponding theophylline salt:theophylline-Z-amino-2-methyl-l-propanol was only 66, under thesame-test conditions. These results are even more startling when themolar proportions. of theophylline per so are considered since one gramof bromotheophylline is equivalent on this basis to only about gram oftheophylline U. S. P.

Amore elaborate series of tests were run substantially as the testhereinbefore described wasrun; and the results obtained are shown on thetable (below), wherein column (1) shows the dosage of the theophyllineor brornotheophyll-ine used in each test, and column (2) showsthepercentage water recovery calculated-by dividing the total volume ofwater given to a cage (of 4 rats each, which is the number of ratsemployed toobtain each test figure on the table) into the volumeof urinecollected in the following 4 hours. Columns ('3); (4), (5) and (6) show,respectively, the total sodium (Na), potassium- (K), chloride (Cl), andsodium plus potassium, in milli-eq'uivalent weights, per cage of fourrats that was found'in the urine recovered during the 4-hour period.Section A shows the results using plain tap water; Section B shows theresults using plain tap water plus the subcutaneous pitressin injectionhereinbefore described; Section C shows the results using plain waterplus pitressin as in'Section'B and also using the amounts of thetheophylline salt specified; and Section 'D compares with Section C,using in this instance the brornotheophylline saltof the inventioninstead of the theophylline salt.

Table SECTION AWATER I Average H d! D SECTION n wsman. rr'rnussnyAverage.. 1a 2. 3. 22

SECTION O-WATER, PITRESSIN, THEOPHYLLINE 2-AMINO- -METHYL-1-PROPANOLAverag e 64 1.32 0.69 1.72 2.51.

T ableContinued Z'AMIN O-2-METHYL-l-PROPANOL Col. 1 Colt: Col; 3 001. 4Col. 5 Col. 6

- I. "TottilMlllieiiulvalent Weight s Percent DoseDrugmgJcc. Water t 1Recovery p v' K" I 761 Nakand 4.84 5.20 4.85 4.23 6.85 as. 3. 7a 2.02 a.as s. so 122 1. as 1.71 2. 22 3.117 126 14s 1.56 2.06 3.04 122 a. as 1.4a a. 5.21; 112 3.4a l.58 3.24 I 5.01

- sst 2.10 ass 5.71 as 5.00 2.40 was 2.40 as 4530 2.25 4.18 v 6.55 21871.94 2.05 4.81. 118 4. 69 2. 17 4. 4s a as 111 3. rs 2. 0s a. 56 5. as

Average 122 l. 93 1. 80 2. O2 3. 73

39 It will be seen from the table-above that in. each instance,

35 be administered to the rats without introducing considerable toxicsymptoms in the'test'animals. it is thus clear that thehromotheophylline'drug gives superior as well as different results,inthat it can'be given in large dosages.

40 Ithas also been found that the instant bromotheophyl- 1 line saltgives a unique physiologicalaction that is-different from the generalaction characteristic of theophylline drugs. It has been establishedthat the major effect of xanthine drugs, including theophylline, is onthe cir- 45 culation, which, in turn, causes increased transportconditions connected with'the waste materials including water and salt.Under appropriate conditions the renal circulation becomes affected, anda diuretic efiect may be obtained; but such action, whether or notdirectly on the renal cells, is, clearly not the major action of thesedrugs. 1

In viewof the fact that the increased renal functionresults, if at allin the case of these drugs, from changes inthe generalized transportsituation, it follows that the renal action induced is variable,depending uponmany 5 other factors afiecting the'transport situationwhichmay divert major transport effects to other areas of the body, suchas the skin.

Tests have revealed that both the theophylline and thebromot-heophylline drugs show an increase intotal weight no loss in atest animal, but that with'the theophylline drug tl1eloss'-may- -beextra-renal as'well-asrena}, whereas in the case of'the instantbromotheophylline drug the losses are almost exclusively renal.Extra-renal weight loss, known to befdue largely totranspiration throughthe 5.3 skin-,is-markediy increased under theophyllineaction in hotweather to such an extent that the renal action may be decreased, orevenmarkedly inhibited, as compared to normal controls. Using-thebromotheophylline drug,

however, this action does not take place, thereby showing p u thatthisdrugpossess'es a unique focussin'g or localizing effect upon kidneyfunction. This function is" valuable because it'providesa newstandardizing agent for corn parative studies on kidney function. Also,tests show that fin hot weather the salt diuresis effectedby-thebremo-76 theophylline drug is consistently high (compared to the The diureticactivity of a compound, as measured by 5 the above test, is a goodindication of its eifectiveness in the relief of premenstrual tensionamong human females.

The relief of premenstrual tension by the diuretic compound of thepresent invention may be' explained when it is appreciated thatpremenstrual tension is a symptomcomplex related to abnormal waterstorage during the premenstrual period and is essentially a Watertoxemia. The intensity of these symptoms varies directly as the amountof water retained, and relief of the symptoms accompanies the diuresis.

6 It will be understood that modifications and variations may beefiected without departing from the scope of the novel concepts ofthe-present invention.

We claim'as our invention: 7

The S-bromotheophylline Saltof Z-aminO-Z-rnethyl-I propanol. v p I I 7References Cited in'the' file of this patent 'UNITED STATES PATENTS2,576,106 Cusicr Nov; 27, 1951 'oTHER REFERENCES

